Cortical Polymicrogyria Research Articles

TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities

The redox state of the neural progenitors regulates physiological processes such as neuronal differentiation and dendritic and axonal growth. The relevance of endoplasmic reticulum (ER)-associated oxidoreductases in these processes is largely unexplored. We describe a severe neurological disorder caused by bi-allelic loss-of-function variants in thioredoxin (TRX)-related transmembrane-2 (TMX2); these variants were detected by exome sequencing in 14 affected individuals from ten unrelated families presenting with congenital microcephaly, cortical polymicrogyria, and other migration disorders. TMX2 encodes one of the five TMX proteins of the protein disulfide isomerase family, hitherto not linked to human developmental brain disease. Our mechanistic studies on protein function show that TMX2 localizes to the ER mitochondria-associated membranes (MAMs), is involved in posttranslational modification and protein folding, and undergoes physical interaction with the MAM-associated and ER folding chaperone calnexin and ER calcium pump SERCA2. These interactions are functionally relevant because TMX2-deficient fibroblasts show decreased mitochondrial respiratory reserve capacity and compensatory increased glycolytic activity. Intriguingly, under basal conditions TMX2 occurs in both reduced and oxidized monomeric form, while it forms a stable dimer under treatment with hydrogen peroxide, recently recognized as a signaling molecule in neural morphogenesis and axonal pathfinding. Exogenous expression of the pathogenic TMX2 variants or of variants with an invitro mutagenized TRX domain induces a constitutive TMX2 polymerization, mimicking an increased oxidative state. Altogether these data uncover TMX2 as a sensor in the MAM-regulated redox signaling pathway and identify it as a key adaptive regulator of neuronal proliferation, migration, and organization in the developing brain.

Response to Heller and Bolz

Response to Heller and Bolz

Craniovertebral junction abnormality in a case of Joubert syndrome

Joubert syndrome (JS) is a genetically heterogeneous autosomal recessive disorder [1] characterized by hypotonia, ataxia, early developmental delay, and characteristic findings on radiographic imaging of the brain. JS has an estimated prevalence of one case in 100,000 [2, 3], and was described in 1969 by Joubert et al. [4]. While there are hallmark features to JS, the phenotypic presentation can vary and overlap with a group of disorders [5] that involve dysfunction in cilia-related proteins [6]. These disorders are known as the ciliopathies and include Bardet–Biedl syndrome (BBS) [7], Meckel–Gruber syndrome (MKS) [2], Senior–Loken syndrome [8], and JS. The ciliopathies frequently present with central nervous system abnormalities that include abnormal cerebellar dysfunction and morphogenesis [9]. Cilia-related genes in the developing cerebellum and pontomedullary junction involve Wnt and sonic hedgehog (Shh) signaling [10] which help to pattern the posterior fossa and brainstem [11]. JS is associated with mutations in a number of genetic loci [3] implicated in cilia-related function [6, 8]. There are several JS subtypes with known genetic loci [2] that present with a variety of CNS anomalies including cerebellar and midbrain dysmorphogenesis and cortical polymicrogyria [8]. Despite the genetic characterization, the underlying mutation frequency for each of the genes associated with JS is less than 10% [3] with fewer than 50% of JS patients having an identified mutation. There are, however, cardinal clinical features that can be used to identify JS patients. They will present most frequently with hypotonia, ataxia, developmental delay, respiratory, or ocular abnormalities [12]. Patients will have characteristic findings on brain MRI including: widened interpeduncular fossa, thickened superior cerebellar peduncles, and hypoplasia of the vermis [13]. We describe a case of a JS patient presenting with craniocervical spine involvement and progressive scoliosis. To the best of our knowledge, this is the first known case describing JS with an associated craniovertebral junction (CVJ) abnormality.

Genotype–phenotype analysis of human frontoparietal polymicrogyria syndromes

Human cerebral cortical polymicrogyria is a heterogeneous disorder, with only one known gene (GPR56) associated with an apparently distinctive phenotype, termed bilateral frontoparietal polymicrogyria (BFPP). To define the range of abnormalities that could be caused by human GPR56 mutations and to establish diagnostic criteria for BFPP, we analyzed the GPR56 gene in a cohort of 29 patients with typical BFPP. We identified homozygous GPR56 mutations in all 29 patients with typical BFPP. The total of 11 GPR56 mutations found represented a variety of distinct founder mutations in various populations throughout the world. In addition, we analyzed five patients with BFPP who did not show GPR56 mutation and found that they define a clinically, radiographically, and genetically distinct syndrome that we termed BFPP2. Finally, we studied seven patients with a variety of other polymicrogyria syndromes including bilateral frontal polymicrogyria, bilateral perisylvian polymicrogyria, and bilateral generalized polymicrogyria. No GPR56 mutation was found in these patients. This study provides a molecular confirmation of the BFPP phenotype and provides the wherewithal for diagnostic screening.

Intracranial angiolipoma as cause of subarachnoid haemorrhage. Case report and review of the literature

A 33-year-old female with a longstanding history of seizures was admitted to our hospital with subarachnoid haemorrhage (SAH). Computed tomography (CT), magnetic resonance imaging (MRI) and digital subtraction angiography (DSA) depicted a vascular fat-containing lesion overlying a right frontal cortical polymicrogyria. The diagnosis of angiolipoma was established. Conservatory management was undertaken with full recovery. She has been followed for 5 years since, with neither re-bleeding nor morphologic change of the lesion. This is a rare intracranial lesion, with only 11 intracranial angiolipomas published in the literature, and is the first case reported which is associated with SAH caused by this lesion.

Mutations in the AHI1 Gene, Encoding Jouberin, Cause Joubert Syndrome with Cortical Polymicrogyria

Joubert syndrome (JS) is an autosomal recessive disorder marked by agenesis of the cerebellar vermis, ataxia, hypotonia, oculomotor apraxia, neonatal breathing abnormalities, and mental retardation. Despite the fact that this condition was described >30 years ago, the molecular basis has remained poorly understood. Here, we identify two frameshift mutations and one missense mutation in the AHI1 gene in three consanguineous families with JS, some with cortical polymicrogyria. AHI1, encoding the Jouberin protein, is an alternatively spliced signaling molecule that contains seven Trp-Asp (WD) repeats, an SH3 domain, and numerous SH3-binding sites. The gene is expressed strongly in embryonic hindbrain and forebrain, and our data suggest that AHI1 is required for both cerebellar and cortical development in humans. The recently described mutations in NPHP1, encoding a protein containing an SH3 domain, in a subset of patients with JS plus nephronophthisis, suggest a shared pathway.

Cerebral white matter involvement in children with mitochondrial encephalopathies.

In childhood mitochondrial encephalopathies the common MRI features are bilateral symmetric abnormalities in basal nuclei and brainstem. The presence of diffuse white matter abnormality has been described only in a few cases. Among a series of 110 children with mitochondrial encephalopathies, 8 patients with MR imaging consistent with a leukoencephalopathy were retrospectively evaluated. Diagnosis was based on the recognition of the biochemical defect in muscle homogenate. H-MR spectroscopic imaging was performed in six of them. Biochemical analysis demonstrated a defect of respiratory chain complexes in six patients: complex I in two cases, complex II in two, complex IV in one, multiple complexes defect in one. Pyruvate dehydrogenase deficiency was demonstrated in two patients. MRI showed severe involvement of the brain white matter without significant basal nuclei or brainstem abnormalities. Two patients developed large cystic areas since onset; in two others progressive vacuolisation of affected white matter was seen later in the course of the disease. One patient with pyruvate dehydrogenase deficiency also presented with a diffuse cortical polymicrogyria. H-MR spectroscopic imaging showed a decrease of N-acetylaspartate, choline and creatine with lactate accumulation in five patients, and was normal in one. These findings suggest that mitochondrial disorders should be included in the differential diagnosis of white matter disorders.

A golgi study of the polymicrogyric cortex in aicardi syndrome

The neuropathological examination of the brain of a 4-month-old girl with Aicardi syndrome (infantile spasms, chorioretinal lacunae, psychomotor retardation, agenesis of the corpus callosum and vertebral anomalies) showed agenesis of the corpus callosum, agenesis of the anterior commissure and abnormal orientation of the hippocampal formation, in addition to periventricular cerebral nodules and extensive non-laminated cortical polymicrogyria of the fronto-parietal regions and gyrus cinguli of both hemispheres. A non-communicating medial supracollicular cyst, racemose cysts of the choroid plexus, underdevelopment of the inferior cerebellar vermis tonsils were also observed. The study of the polymicrogyric cortex with the Golgi method revealed an abnormal orientation of neurons; but the different varieties of cells were located at the depth corresponding to that were they are normally found. The Golgy study of the periventricular nodules disclosed the presence of different types of cortex-like neurons. On the basis of these data it may be suggested that polymicrogyria is not a migratory disturbance, but rather the result of a partial necrosis of the cortical mantle occurring before the 5th month of foetal life.